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Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda DEATH DUE TO CHD IN THE USA IN 1986 BUSH, ANN NY ACAD SCI,1990.

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Presentation on theme: "Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda DEATH DUE TO CHD IN THE USA IN 1986 BUSH, ANN NY ACAD SCI,1990."— Presentation transcript:

1 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda DEATH DUE TO CHD IN THE USA IN 1986 BUSH, ANN NY ACAD SCI,1990

2 PROCAM (MÜNSTER HEART STUDY): MENOPAUSE AND LIPID RISK FACTORS IN 45 TO 55 YEARS OLD WOMEN Pre-Menopause Menopause P (n = 1537)(n = 2456) age (years)48.3 ± ± 3.0< BMI (kg/m 2 )25.8 ± ± 4.5< cholesterol (mg/dL) 221 ± ± 41< triglycerides (mg/dL)* 88 99< LDL-C (mg/dL) 143 ± ± 38< HDL-C (mg/dL) 59 ± ± 16n.s. chol./HDL-C ratio4.02 ± ± 1.32< *: geometric mean, n.s.: not significant

3 PROCAM (MÜNSTER HEART STUDY): MENOPAUSE AND HEMOSTATIC RISK FACTORS IN 45 TO 55 YEARS OLD WOMEN Pre-Menopause Menopause P (n = 229) (n = 307) fibrinogen (mg/dL) 265 ± ± 56< D-dimer (mg/l)* n.s. factor VIIc(mg/dL) 108 ± ± 34< protein C(%) 111 ± ± 24< plasminogen (%) 104 ± ± 14< 0.05 PAI-1 (U/l)* < 0.05 vWF(%) 103 ± ± 31 n.s. CRP (mg/dL)* < 0.05 *: geometric mean

4 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda MAJOR RISK FACTORS FOR CHD AGE > 45 Y MALES AND > 55 Y FEMALES Family history of MI or sudden death: < 55 males < 65 females Cigarettes smoke Elevated blood pressure HDL-C < 35 mg/dL Diabetes mellitus HDL-C > 60 mg/dL NATIONAL CHOLESTEROL EDUCATION PROGRAM. CIRCULATION 1994;89:

5 POSTMENOPAUSAL ESTROGEN/PROGESTIN INTERVENTIONS TRIAL (PEPI) 875 HEALTHY POST-MENOPAUSAL WOMEN AGE PARALLEL INTERVENTION GROUPS: Placebo CEE mg/d CEE mg/d + MPA 10 mg/d x 12 d/mo CEE mg/d + MPA 2.5 mg/d CEE mg/d + MP 200 mg/d x 12 d/mo ENDPOINTS: HDL-C Systolic blood pressure Fibrinogen Insulin JAMA 1995;273:199 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda

6 PEPI TRIAL RESULTS LIPOPROTEINS: –HDL-C increased in all active treatments (Greatest with CEE and CEE + MP) –LDL-C decreased equally in all treatment groups –Triglycerides increased equally in all treatment groups SYSTOLIC BLOOD PRESSURE: increased similarly in all treatment groups INSULIN: no difference in fasting or 2-hour insulin among all treatment groups FIBRINOGEN: no difference among active treatment groups JAMA 1995;273:199 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda

7 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda EFFECTS OF ORAL ESTROGENS ON SERUM LIPOPROTEINS IN POSMENOPAUSAL WOMEN BRANCHI A., 1998

8 PEPI Trial Results LIPOPROTEINS: –HDL-C increased in all active treatments (Greatest with CEE and CEE + MP) –LDL-C decreased equally in all treatment groups –Triglycerides increased equally in all treatment groups SYSTOLIC BLOOD PRESSURE: increased similarly in all treatment groups INSULIN : No difference in fasting or 2-hour insulin among all treatment groups FIBRINOGEN: No difference among active treatment groups JAMA 1995;273:199 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda

9 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda ANTIATHEROGENE PROPERTILE OF ESTROGENS Reduced proliferation of SMC and neo intima formation Reduced production of collagen and elastin Modulation of vasomotor response Increased coronary responsed to vasodilatory stimuli Increased prostacyclyn production by SMC Reduction of plasma homocysteine levels

10 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda RELATIVE RISK AND 95% CI FROM STUDIES OF ESTROGEN USE TO PREVENT CHD STAMPFER, NEJM, 1991 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda

11 THE NURSES HEALTH STUDY: CHD RISK AND POSTMENOPAUSAL ESTROGEN + PROGESTIN USE 59,337 women, age 30-55, followed for 16 years Relative risk for CHD events in current estrogen users was 0.60, and current estrogen + progestin users was 0.39 Length of HRT did not change risk reduction Estrogen doses of 0.3 and mg had the greatest benefit Women years old had as much benefit as younger women NEJM 1996;335:453 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda

12 ESTROGEN REPLACEMENT IN POSTMENOPAUSAL WOMEN: NCEP RECOMMENDATIONS Observational information suggests lower CHD risk in women on HRT Experimental data suggests estrogen has beneficial effects on endothelial function Oral estrogen can lower LDL-C and increase HDL-C NCEP recommends that estrogen replacement can be used as alternative or adjunctive treatment to manage hypercholesterolemia in postmenopausal women. Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda

13 HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY (HERS) Randomized, placebo-controlled trial of E/P therapy vs. placebo in 2,763 women with CHD; average age 67 years Treatment was mg CEE* mg medroxyprogesterone daily for 4 years Primary endpoint: nonfatal MI and CHD death Secondary endpoints: CABG, PTCA, unstable angina, CHF, PVD, TIA *CEE = conjugated equine estrogen; JAMA 1998;280: Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda

14 HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY (HERS) CHANGES IN LIPID LEVELS AT 1 YEAR LDL-CHDL-CTG Mean % change from baseline Placebo Estrogen/progestin *P < HULLEY S ET AL. JAMA 1998;280:605– * -2 8* 10* 2 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda

15 THE HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY (HERS) INCIDENCE OF CHD EVENTS IN TREATMENT AND PLACEBO GROUPS Follow-up (years) HULLEY ET AL. JAMA 1998; 280: Placebo (n=1383) Estrogen/Progestin (N=1380) CHD Death + Nonfatal MI CHD Death Coronary Revascularisation or Unstable Angina Incidence (%) RH = 0.99 p = 0.91 RH = 0.99 p = 0.46 RH = 1.24 p = 0.23 RH = 0.88 p = 0.15

16 HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY (HERS) CUMULATIVE INCIDENCE OF PRIMARY CHD EVENTS (2,763) 1 (2,631) 2 (2,506) 3 (2,392) 4 (1,435) 5 (113) Incidence (%) Follow-up, y (No. at risk) Estrogen/progestin Placebo Hulley S et al. JAMA 1998;280:605–613 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda

17 SIDE-EFFECTS IN HERS STUDY HULLEY ET AL. JAMA 1998; 280: Side-effects confirmed venous thrombosis deep vein thrombosis pulmonary embolus fatal pulmonary Embolus gallbladder disease oestrogen/ progestin (n=1380) placebo (n=1383) relative risk P value

18 JAMA 1998;280: HERS RESULTS No statistically significant difference between HRT and placebo in both primary and secondary endpoints after 4 years. Within first year, greater incidence in CHD events in HRT group. In years 3 and 4, lower CHD events in HRT group compared to placebo. HRT lowered LDL 11% and increased HDL 10% compared to placebo. Approximately 50% of randomized women were on lipid-lowering drugs. Higher incidence of VTE and cholelithiasis in HRT group. Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda

19 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY (HERS II) The higher risk of developing CHD in HERS was in the first two years of therapy. A decline occured between year 3 and 5. HERS II was designed to verify whether the tendency to a reduction of CHD in HERS persisted in a longer follow up. The HERS II study recruited women (average 67 yearsof age) who gave their informed consent to continue therapy with the active drug or placebo. GRADY ET AL., JAMA 2002

20 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY (HERS II) JAMA, 2002

21 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda NON CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY (HERS II) 1 JAMA, 2002

22 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda NON CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY (HERS II) 2 JAMA, 2002

23 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda RISK AND BENEFITS OF ESTROGEN PLUS PROGESTIN IN HEALTHY POSTMENOPAUSAL WOMEN Principal Results from the Womens Health Initiative Randomized Controlled Trial A randomized controlled primary prevention trial (planned duration 8.5 years) in which 16,608 postmenopausal women aged years with an intact uterus at baseline were recruited by 40 US clinical centers in Participants received conjugated equine estrogens, mg/d, plus medroxyprogesterone acetate, 2.5 mg/d or placebo JAMA, 2002

24 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda 8,506 assigned to Estrogen+Progestin 8,102 assigned to placebo Status on April 30, ,968 alive 307 unknown vital status 231 deceased Status on April 30, ,608 alive 276 unknown vital status 218 deceased PROFILE OF THE ESTROGEN+PROGESTIN COMPONENT OF THE WOMENS HEALTH INITIATIVE 373,092 women initiated screening 18,845 provided consent and reported no isterectomy 16,608 randomized

25 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda WHI: CLINICAL OUTCOMES 1 JAMA, 2002

26 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda WHI: CLINICAL OUTCOMES 2 JAMA, 2002

27 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda WHI: CLINICAL OUTCOMES 3 JAMA, 2002

28 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda WHI: CAUSE OF DEATH JAMA, 2002

29 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda CONCLUSIONS Overall health risk exceeded benefits from use of combined estrogen+progestin for an average 5.2 year follow-up among healthy postmenopausal women Risk for CHD was largely limited to the 1° year of therapy, whereas risk for Stroke and Venous Thromboembolism continued throughout the 5 years of therapy and may reflect prothrombotic and proinflammatory effects of progestins Risk for breast cancer was associated with the duration of treatment The risk-benefit profile of combined HRT is not consistent with the requirements for primary prevention of chronic diseases

30 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda MENOPAUSAL HORMONE REPLACEMENT THERAPY AND RISK OF OVARIAN CANCER Study Design: cohort study on post menopausas women Aim: to address whether the estrogen + progestin treatment could modify the risk of developping ovary cancer LACEY, JAMA 2002

31 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda HORMONAL REPLACEMENT THERAPY AND OVARIAN CANCER No therapyEstrogens Estrogens+ Progestins Years-person N° of ovarian cancer Relative Risk ( ) 1.1 ( ) LACEY, JAMA 2002

32 INTERVENTION STUDIES AIMED AT THE PREVENTION OF CORONARY HEART DISEASE (SUBGROUPS OF WOMEN) 4S: The Lancet 1994;344: Care: Sacks FM et al. N Engl J Med 1996;335: AFCAPS/TexCAPS: Downs JR et al. JAMA 1998;279:

33 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda SIMVASTATIN: SECONDARY ENDPOINT STATIN worse Relative Risk IC 95% SIMVAPLACEBOGROUPS (10269)(10267) SIMVA betterPlacebo better AGE (YEAR) Het 2 3 = 4.4 < > GENDER Het 2 1 = 0.4 Male Female All patients (19.9%)(25.4%) 24%SE 2.6 (2P< ) VASCULAR EVENTS BY AGE AND GENDER

34 Società Italiana per lo Studio dell Aterosclerosi Sez. Regionale Lombarda HORMONAL REPLACEMENT THERAPY (WHEN TO BE USED) Menopausal symptoms (vasomotor, urogenital or vaginal atrophy, mood disturbance) High risk of osteoporosis Early menopause


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